What is Cancer / Breast Cancer?

Cancer is a group of over 100 diseases characterized by uncontrolled cell growth due to DNA mutations. These mutations disrupt normal processes such as cell survival, death, and tissue regulation. Cancer cells form tumors, which can invade nearby tissues and spread throughout the body via the blood or lymphatic system. Some hallmarks of cancer include continuous proliferation, resistance to cell death, invasion, metastasis, and the ability to trigger blood vessel growth (angiogenesis). [1] Breast cancer arises from uncontrolled growth in breast cells, primarily from the ducts or lobules, and is categorized as ductal or lobular carcinoma. [2] Though most cases affect women, men can also develop BC. Mutations in key genes that regulate cell growth lead to cancer formation, causing the creation of abnormal cells that divide uncontrollably. BC can manifest as benign tumors (non-cancerous) or malignant tumors (cancerous), with malignant tumors having the potential to invade tissues and spread throughout the body. [3] [4]

HISTORY OF BC: FROM ANCIENT TIMES TO THE 20TH CENTURY: 

Ancient Egypt and Greece: BC was documented over 3,500 years ago. The Greek physician Hippocrates described cancer as being caused by an excess of "black bile" and named it *karkinos* (crab) due to the crab-like appearance of tumors. He believed surgery was ineffective. [5]

17th and 18th Century: Medical perspectives evolved as physicians began to reject Hippocrates' humoral theory. François Sylvius suggested cancer resulted from chemical changes in body fluids, and Bernardino Ramazzini associated the high prevalence of BC in nuns with sexual inactivity. The idea of surgery emerged during this period, with Henri Le Dran suggesting the removal of tumors and lymph nodes as a potential treatment. [6]

The 19th and 20th Century: Surgical Advancements: By the mid-19th century, surgery became the primary option for treating BC. William Halsted introduced radical mastectomy, an aggressive surgery that removed the breast, lymph nodes, and chest muscles in one piece to prevent cancer spread. This procedure became the standard treatment but had severe side effects, such as disfigurement, lymphedema, and chronic pain. In the 20th century, advancements in anesthesia, antiseptic techniques, and blood transfusions improved surgical outcomes. However, the disfiguring nature of radical mastectomy discouraged many women from undergoing the procedure. In the 1970s, treatment expanded to include chemotherapy, radiation, or a combination of both, providing more options for patients. [7]

KEY RISK FACTORS FOR BREAST CANCER: 

• Gender: Women are at much higher risk than men.
• Age and Menopause: Risk increases with age, especially post-menopause.
• Hormonal Factors: Early menarche, late menopause, late childbirth, and short breastfeeding duration raise BC risk.
• Family History: Having first-degree relatives with BC increases personal risk.
• Genetic Mutations: Mutations in genes like BRCA1, BRCA2, TP53, PTEN, and CHEK2 raise BC susceptibility.
• Weight: Being overweight after menopause increases risk by elevating estrogen and insulin levels.
• Smoking and Alcohol: Long-term smoking and alcohol consumption significantly raise BC risk.
• Benign Breast Conditions: Some non-cancerous breast conditions, like atypical hyperplasia, can raise BC risk.

Additional Risk Factors 

• Exposure to Diethylstilbestrol (DES) or oral contraceptives: It may slightly increase BC risk.
• Environmental Chemicals: Like with estrogen-like properties may have an influence.
• Night Work: Disruption of melatonin levels may contribute to BC risk.
• Physical Activity: Regular exercise reduces risk.
• Controversies: No confirmed link between antiperspirants, abortion, or breast implants and BC risk.

Race and Ethnicity 

White women have a slightly higher incidence of BC, but African-American women face higher mortality rates. BC is more common among younger African-American women, while Asian, Hispanic, and Native-American women have lower risks overall. [8]

Signs and Symptoms of Breast Cancer

The most common symptom of BC is a new lump or mass. A painless, hard mass that has irregular edges is more likely to be cancerous, but BCs can be tender, soft, or rounded. They can even be painful. For this reason, it is important to have any new breast mass or lump or breast change checked by a health care professional experienced in diagnosing breast diseases.

Other possible signs of BC include:

• Swelling of all or part of a breast (even if no distinct lump is felt)
• Skin irritation or dimpling
• Breast or nipple pain
• Nipple retraction (turning inward)
• Redness, scaliness, or thickening of the nipple or breast skin
• Nipple discharge (other than breast milk)

Sometimes a BC can spread to lymph nodes under the arm or around the collar bone and cause a lump or swelling there, even before the original tumor in the breast tissue is large enough to be felt. Although any of these symptoms can be caused by things other than BC [9].

MOLECULAR PROFILING AND PROGNOSTIC IMPLICATIONS IN BREAST CANCER:

Cancer progression is highly variable, with metastatic spread being a critical factor in patient prognosis. Although metastasis inevitably occurs in many untreated cancer cases, the course of disease progression differs among individuals. Identifying patient subgroups with a heightened metastatic potential is vital for reducing mortality. To address this challenge, recent advancements in gene-expression profiling have categorized breast cancer into four major molecular subtypes: basal-like, luminal-A, luminal-B, and HER2-positive cancers. Of these, basal-like breast cancers exhibit the most aggressive clinical behavior and the poorest survival outcomes. [10]

These molecular classifications align with the expression status of key biomarkers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Notably, basal-like breast cancers are often identified as "triple-negative" tumors, characterized by the absence of ER, PR, and HER2 expression. These tumors are notoriously difficult to treat and are associated with poor clinical outcomes. Although these molecular subtypes offer insights into survival patterns, the heterogeneity of gene expression within these groups complicates their use in precise prognostic evaluations. [11]

Cyclin D1 and β-catenin:

Cyclin D1 and β-catenin play pivotal roles in the pathogenesis and progression of invasive ductal carcinoma (IDC), the most common subtype of breast cancer, accounting for nearly 80% of all breast cancer diagnoses. IDC is characterized by its aggressive behavior and ability to invade surrounding breast tissue, which underscores the importance of understanding molecular markers that contribute to its invasiveness and metastatic potential. [12] Cyclin D1, a cell cycle regulator encoded by the CCND1 gene, promotes the G1 to S phase transition by activating cyclin-dependent kinases (CDKs). Aberrant expression of Cyclin D1 has been linked to unchecked cell proliferation, a hallmark of cancer. In breast cancer, overexpression or amplification of Cyclin D1 is frequently observed, particularly in cases of hormone receptor-positive subtypes, suggesting its involvement in tumorigenesis and association with tumor aggressiveness. This overexpression can drive the cancerous transformation of mammary epithelial cells, significantly impacting patient prognosis. [11]

β-Catenin, on the other hand, is a multifunctional protein encoded by the CTNNB1 gene. It plays a dual role as both a crucial mediator in cell-cell adhesion and a core component of the Wnt signaling pathway, which is known to regulate cellular proliferation, differentiation, and apoptosis. In the Wnt signaling pathway, β-catenin stabilization and nuclear translocation lead to the activation of transcriptional programs that promote oncogenesis. [13] Abnormal β-catenin signaling, often due to mutations or dysregulated pathway components, can contribute to IDC progression by enhancing proliferative signals, promoting invasive behavior, and enabling metastasis. β-Catenin’s interaction with Cyclin D1 is particularly relevant in IDC, as Wnt/β-catenin signaling is known to regulate Cyclin D1 expression, creating a feed-forward loop that drives tumor growth and invasive potential. This interplay suggests that co-evaluation of Cyclin D1 and β-catenin could offer valuable insights into IDC biology and potentially reveal new avenues for targeted therapeutic strategies. [14]

Historically, research has demonstrated the importance of molecular markers such as HER2, estrogen receptor (ER), and progesterone receptor (PR) in IDC diagnosis and treatment, revolutionizing breast cancer prognosis through targeted therapies. [15] However, resistance to these therapies and relapse rates in IDC necessitate further exploration of other molecular markers. Recent studies in breast cancer have increasingly focused on Cyclin D1 and β-catenin as emerging targets, especially given their intricate involvement in cancer cell proliferation and invasion. An understanding of Cyclin D1 and β-catenin’s role in IDC, therefore, may not only contribute to a more comprehensive biomolecular profile but could also guide the development of combination therapies that improve patient outcomes, thus expanding on past advancements in breast cancer research. [16]

The Wnt Signaling Pathway:

The Wnt signaling pathway plays a pivotal role in various biological processes, including embryonic development, stem cell regulation, and tumor cell survival. One of its key components, beta-catenin (β-catenin), serves dual roles. In its cytoplasmic form, β-catenin interacts with E-cadherin to maintain cell adhesion, anchoring the cytoskeleton to the cell membrane. Alternatively, nuclear β-catenin binds with T-cell factor/lymphoid enhancer factor (Tcf/Lef), triggering the transcription of genes involved in cell cycle regulation, such as cyclin D1. [15]

The upregulation of cyclin D1 promotes progression through the G1 phase of the cell cycle, which has been implicated in mammary gland hyperplasia. Dysregulation of β-catenin, therefore, plays a significant role in the development and progression of breast tumors. [16]

The study focuses on evaluating cancer markers among female patients with Invasive ductal carcinoma (IDC). A total of 150 specimens were collected for analysis. The primary objective was to explore tumor characteristics and establish significant associations between tumor markers and disease progression. This study was conducted at Rawalpindi, Pakistan, with samples collected from different Cancer hospital and histological center. Ethical approval was obtained from the respective Institutional Review Boards of these hospitals prior to the collection of specimens. The tumors were classified according to the 6th edition of the AJCC Cancer Staging Manual, ensuring consistency with international cancer staging protocols. The review of each report of lymph node metastasis (LNM) status of each patient was assessed through immunohistochemical (IHC) staining, involving at least ten lymph node dissections per patient was thoroughly reviewed. We include the sample which ensure that each sample contained more than 95% tumor cells. Each sample yielded approximately 2,500–3,000 tumor cells, which were further processed for RNA isolation. Paired adjacent non-cancerous cells were collected using the same procedure to serve as controls. For the IHC studies, fresh-frozen tissue sections and normal routine histological biopsies report were reviewed.

The staining intensity and tumor area coverage were scored as follows:

Tumor cell coverage:

• 0 = Negative
• 1 = <10%
• 2 = 10–50%
• 3 = >50%

Staining intensity:

• 0 = None/Weak
• 1 = Moderate
• 2 = Strong

A scoring index (product of staining intensity and coverage) was used to determine overexpression events. A cutoff score greater than 4 was considered significant. The study employed frequency and percentage analysis to explore tumor characteristics among the collected specimens. Associations between tumor markers (cyclin D1 and β-catenin) and clinicopathological features were evaluated to assess their potential as prognostic biomarkers for Invasive ductal carcinoma (IDC). The findings from this study contribute to a cooperative effort aimed at identifying cancer markers that provide insights into breast cancer progression. This research offers significant implications for the early detection and prognosis of breast cancer, ultimately supporting better clinical management of female patients with IDC in the Pakistani healthcare context.

Patient Demographics by Age

The female patients with Invasive ductal carcinoma were aged between 25 to 87 years, with a mean age of 50.6 years (±11.6 SD). For better clarity, the age distribution is divided into the following sub-ranges:

Table: 01: Patient demographic by Age distribution

This wide age range reflects the variable occurrence of Invasive ductal carcinoma across both younger and older populations, with the majority concentrated between 36 and 55 years.

Tumor Characteristics

The tumor characteristics of the patients were evaluated based on tumor size, grade, and stage:

Table: 02: Frequency of Tumor Characteristics

The majority of tumors were classified as stage I or II, indicating the presence of localized disease in most patients. A significant portion of the tumors were moderate-grade (Grade II), suggesting intermediate aggressiveness in this cohort.

Lymph Node Metastasis (LNM) and IHC Markers

The presence of lymph node metastasis (LNM) and expression of key immunohistochemical (IHC) markers were also assessed:

Table: 03: Frequency of Lymph Node Metastasis (LNM) and IHC Markers

More than half of the patients had HER2-positive tumors (54.8%), a marker associated with more aggressive disease and often requiring targeted therapies like trastuzumab. Hormone receptor status showed variability, with a slightly higher proportion of ER-negative (54.5%) and PR-negative (57.1%) patients.

Expression of Cyclin D1 and β-Catenin

The frequency and percentage of three molecular markers—Cyclin D1 and β-Catenin were analyzed as follows:

Table: 04: Frequency of Expression of Cyclin D1 and β-Catenin

These molecular markers are known to play key roles in cell cycle regulation, tumor progression, and metastasis. Cyclin D1 was highly expressed (60%), indicating active cell proliferation in a majority of the tumors. The expression of β-Catenin was lower (33.3%), aligning with its variable role in breast cancer pathogene

This section delves into the significance of the clinical and molecular characteristics observed in female patients with Invasive ductal carcinoma (IDC) in the context of other global studies. The findings are analyzed in detail concerning tumor size, grade, stage, lymph node metastasis (LNM), receptor expression, and the potential role of molecular markers, with comparisons to published literature.

The mean age of 50.6 years in our cohort aligns with global trends, where breast cancer incidence peaks between 50 and 60 years. Studies show that younger patients (<40 years) present with more aggressive tumors, resulting in poorer prognosis. [14] In contrast, older age groups tend to have hormone receptor-positive tumors, which are generally more responsive to endocrine therapies. Globally, the age of presentation varies, with studies from Western countries reporting a mean diagnostic age of around 53 years, while in Asian populations, the mean age is slightly lower, possibly due to genetic and environmental differences. [15] In our study, the highest prevalence was observed between the ages of 36 and 55 years, consistent with other research showing peak incidence in middle age. [16] Younger patients (<35 years) often exhibit aggressive, hormone receptor-negative subtypes, contributing to worse outcomes and higher recurrence rates​. [15] Tumor size and grade are established predictors of prognosis in breast cancer. In this study, 76.7% of patients had tumors smaller than 30 mm, indicating early-stage detection in most cases. Smaller tumor size is associated with favorable outcomes, as seen in multiple studies emphasizing the role of early detection through mammographic screening. [16] However, 23.3% of patients had tumors larger than 30 mm, which aligns with findings that larger tumors are more likely to have lymph node involvement and require aggressive management. [17] The distribution of tumor grades—24% grade I, 46.7% grade II, and 29.3% grade III—corresponds with global data. Moderate-grade (grade II) tumors are the most common, presenting a challenge for prognosis as they display intermediate behavior. High-grade tumors (grade III) are often associated with rapid progression and increased recurrence. [18] The predominance of grade III tumors in younger patients further emphasizes the aggressive nature of breast cancer in this demographic. [19] [20] In terms of stage, the majority of patients presented with stage I (39.3%) or stage II (42.7%) tumors. This finding is consistent with developed healthcare systems, were widespread screening leads to earlier detection. However, the presence of stage III (14.7%) and IV (3.3%) tumors highlights the need for continued improvements in early detection programs, particularly for underserved populations. [21] Our data indicate that 39.3% of patients had positive lymph node involvement (N1/N2), which aligns with reports showing that LNM occurs in about 40-50% of breast cancer cases globally. [22] Lymph node status is a critical prognostic factor, with positive nodes correlating with higher recurrence rates and lower survival. [23] Research consistently shows that patients with negative LNM (60.7% in our study) have better disease-free survival and overall outcomes. [24]

The receptor status of tumors plays a pivotal role in determining prognosis and therapeutic options. In our cohort, ER positivity was found in 45.5% of tumors, and PR positivity in 42.9%, which is comparable to global trends where approximately 60-70% of breast cancers express these hormone receptors. [25] Hormone receptor-positive tumors generally respond well to endocrine therapy, leading to better outcomes. However, the relatively high proportion of ER-negative (54.5%) and PR-negative (57.1%) cases suggests an aggressive disease profile, which aligns with studies that report poor prognosis in hormone receptor-negative subtypes​. [26] HER2 overexpression, seen in 54.8% of our cases, is higher than reported in some studies, which generally indicate that 15-20% of breast cancers are HER2-positive. [27] HER2-positive tumors are associated with aggressive behavior but respond well to targeted therapies like trastuzumab, which improves survival outcomes when included in treatment regimens (NCI, 2023). The co-expression of HER2 with hormone receptor negativity further complicates management and emphasizes the need for multimodal treatment approaches. [28]

Cyclin D1 and β-Catenin have been identified as emerging markers with potential prognostic and therapeutic implications. In our study, 60% of tumors showed Cyclin D1 overexpression, a finding consistent with research indicating that Cyclin D1 is overexpressed in ER-positive tumors, promoting cell cycle progression and proliferation. [28] Cyclin D1 overexpression has also been associated with improved prognosis, particularly in tumors that respond to endocrine therapy. [29] β-Catenin, a marker involved in the Wnt signaling pathway, was expressed in 33.3% of our cases. While β-Catenin is often linked to aggressive behavior and poor outcomes, its role in breast cancer remains complex, with studies suggesting both oncogenic and tumor-suppressive functions depending on the cellular context. [30]

The findings of this study contribute valuable insights into the clinical and molecular characteristics of IDC. The age distribution, tumor size, grade, and receptor status align with global trends, underscoring the importance of early detection and personalized treatment. However, the presence of aggressive molecular subtypes and high rates of receptor-negative tumors highlight the need for advanced diagnostic strategies and targeted therapies. The integration of molecular markers like Cyclin D1 and β-Catenin into clinical practice holds promise for improving prognostic predictions and tailoring treatments. Future research should focus on validating these markers and exploring new therapeutic options, particularly for triple-negative and HER2-positive breast cancers. Continued efforts to enhance screening programs and expand access to targeted therapies will be essential in reducing disparities and improving outcomes for all patients worldwide.

Conflict Of Interest

Authors have no conflict of interest.

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