Fluctuation of HER2 expression in breast carcinomas during the menstrual cycle

Abstract

The hormonal milieu at time of tumor surgery seems to have a significant impact on survival in premenopausal breast cancer patients. Indeed, surgery performed during the follicular phase of the menstrual cycle was suggested to correlate with a poor prognosis. To investigate the relationship between prognosis and menstrual cycle at time of surgery, we analyzed the expression of some markers associated with tumor aggressiveness, such as the hormone receptors, HER2, p53, Bcl2, and cathepsin D in breast carcinomas obtained from 198 premenopausal women who underwent surgery during different phases of the menstrual cycle. HER2 overexpression was found to fluctuate in hormone receptor-positive tumors. In actual fact, 20% of the tumors removed during the follicular phase scored HER2-positive, versus 8% of those removed during the luteal phase. Similarly, a number of hormone receptor-positive tumor specimens, obtained from the same patients during follicular and luteal phases, were scored HER2-positive when the sample was removed during the follicular phase and HER2-negative when removed in the luteal phase. Southern blot analysis of the HER2 gene indicated that, in hormone receptor-positive cases, the overexpression of HER2 is often not associated with gene amplification. The finding that overexpression of the HER2 gene, associated with tumor aggressiveness, can fluctuate according to the hormonal milieu may explain the increased survival of patients operated during the luteal phase. It is also relevant to the selection and treatment of patients most likely to benefit from anti-HER2 antibody therapy.

Figure 1.

Frequency of HER2 overexpression according to the menstrual phase at time of surgery. Total series (▴, 198 cases); hormone receptor-positive cases (▪, 134 cases, including 8, 42, 29, 55 cases in the four menstrual phases, respectively); hormone receptor-negative cases (•, 64 cases, including 6, 18, 15, 25 cases in the four menstrual phases, respectively).

Figure 2.

Immunohistochemical analysis of HER2 expression in two cases of breast carcinomas. Top: Case 1 removed during follicular phase (A; magnification ×220), and luteal phase (B; magnification ×180). Middle: Case 2 removed during follicular phase (C; magnification ×95, inset ×180) and luteal phase (D; magnification ×95). Bottom: Case 3 removed during follicular phase (E; magnification ×180) and luteal phase (F; magnification ×180).

Figure 3.

Southern blot analysis of DNA isolated from the indicated sources. Ten micrograms of DNA was digested with EcoRI and hybridized with full-length c-erbB2 cDNA. Lanes: 1, 3, and 5, tumors ER negative; 2 and 4, tumors ER positive. Phage λ HindIII size markers in kilobases are indicated to the right.